Laparoscopic surgery represents a new paradigm, with less pain, quicker recovery times, and reduced disability. In time, most general surgical procedures will be performed in this manner. Laparoscopic surgery is not simply a reduced surgical insult, it is a different surgical insult. Preliminary data in the rat shows that a pneumoperitoneum with CO2 gas alters the inflammatory response associated with laparoscopic surgery in the setting of sepsis. The objective of this application is to establish whether CO2 pneumoperitoneum has a modifying role, and to determine the possible mechanism(s). AIM 1: To test whether CO2 modifies the inflammatory response during laparoscopic surgery. The effect of pneumoperitoneum with CO2, helium, or air on the inflammatory response after sepsis (cecal ligation and puncture) will be compared. The parameters of the inflammatory response to be evaluated are: leukocytosis, leukocyte infiltration, hepatic acute phase gene expression, and circulating levels of cytokines. AIM 2: To determine where in the pathway of the inflammatory response CO2 pneumoperitoneum exerts its effect. Expression of the acute phase proteins will be used as an experimental paradigm. Pre-transcriptional, transcriptional, and post transcriptional regulation of the acute phase genes will be evaluated. AIM 3: To determine how the C02 pneumoperitoneum alters the inflammatory response. The hypothesis of this aim is that alteration of pH with abdominal distension alters the inflammatory response. A) Arterial pH will be measured to correlate pH changes with immune modulation. B) The pH will be artificially decreased by a comparable amount via systemic intravenous infusion of hydrochloric acid in the setting of sepsis plus C02 pneumoperitoneum, helium pneumoperitoneum, air pneumoperitoneum, and open surgery. The information provided by this investigation will be essential in patient care as increasing numbers of patients undergo operations using the CO2 pneumoperitoneum.